Centers for Disease Control and Prevention

National Center for Emerging and Zoonotic Infectious Diseases

Partial Evidence to Recommendations 

Framework for Dengue Vaccine TAK-003

Joshua Wong, MD

ACIP June 22, 2023

Dengue Branch, CDC
Goals for Partial EtR Presentation

• Summarize the extent of the Work Group deliberations to date

• Present three Evidence to Recommendations (EtR) domains*

• Prepare ACIP for the next meeting which will include a full EtR presentation, 

proposed recommendation, and vote.† During the full EtR presentation:

• Domains presented today will be summarized.

• Work Group opinions and relevant summaries of straw polls will be presented.

*Data from ND/CDC Modeling are preliminary and subject to change

†Subject to change
Evidence to Recommendations (EtR) Framework

EtR Domain Question

Public Health Problem • Is the problem (dengue) of public health importance?

Benefits and Harms

• What is the overall certainty of this evidence for the critical outcomes? 

• How substantial are the desirable anticipated effects of the intervention (TAK-003

dengue vaccine)?

• How substantial are the undesirable anticipated effects?

• Do the desirable effects outweigh the undesirable effects?

Values

• Does the target population feel the desirable effects are large relative to the 

undesirable effects?

• Is there important variability in how patients value the outcomes?

Acceptability • Is the intervention acceptable to key stakeholders?

Feasibility • Is the intervention feasible to implement?

Resource Use • Is the intervention a reasonable and efficient allocation of resources?

Equity • What would be the impact of the intervention on health equity?
Public Health Problem

Is the problem (dengue) of public health 

importance?
Is dengue a problem of public health 

importance in dengue-endemic areas?

1. Should two doses of TAK-003 be administered routinely to seropositive* 

persons aged 4–16 years living in dengue-endemic areas?

2. Should two doses of TAK-003 be administered routinely to seronegative 

persons aged 4–16 years living in dengue-endemic areas?

3. Should two doses of TAK-003 be administered routinely to seropositive* 

persons aged 17–60 years living in dengue-endemic areas?

4. Should two doses of TAK-003 be administered routinely to seronegative 

persons aged 17–60 years living in dengue-endemic areas?

*Recommendations for seropositive individuals only will require prevaccination screening for previous dengue virus infection.
Dengue is endemic in six U.S. territories and 

freely associated states.
Puerto Rico has the largest population 

among territories with endemic dengue.

2020 data - census.gov 

Territory Population (%)

Puerto Rico 3,285,874 (96.0%)

US Virgin Islands 87,146 (2.5%)

American Samoa 49,710 (1.5%)

Total population at risk 3,422,730 (100%)
0

2000

4000

6000

8000

10000

12000

1 2 3 4 5 6 7 8 9 10 11

Number of cases

Series1 Series2 Series3

0

2

4

6

8

10

12

1 2 3 4 5 6 7 8 9 10 11

Incidence per 1,000 population

Series1 Series2 Series3

Dengue cases and rates per 1,000 population

in Puerto Rico, American Samoa, and USVI, 2010–2020 

Ryff KR, Rivera A, Rodriguez DM, Santiago GA, Medina FA, Ellis EM, Torres J, Pobutsky A, Munoz-Jordan J, Paz-Bailey G, Adams 

LE. Epidemiologic Trends of Dengue in U.S. Territories, 2010-2020. MMWR Surveill Summ. 2023 May 19;72(4):1-12.
Seropositive Seronegative

4–16 years

Children/Adolescents

17–60 years

Adults

Is dengue a problem of public health importance 

for children/adolescents living in endemic areas?

*Immunogenicity in seropositive adults is expected to be at least as high as in seronegative adults.
Dengue cases and hospitalizations by age group in 

Puerto Rico, 2010–2020

Highest case rates occurred among children 10–19 years old

Ryff KR, Rivera A, Rodriguez DM, Santiago GA, Medina FA, Ellis EM, Torres J, Pobutsky A, Munoz-Jordan J, Paz-Bailey G, Adams 

LE. Epidemiologic Trends of Dengue in U.S. Territories, 2010-2020. MMWR Surveill Summ. 2023 May 19;72(4):1-12.
Dengue cases and hospitalizations by age group in 

US Virgin Islands and American Samoa, 2010–2020

Highest case rates occurred among children 10–19 years old

Ryff KR, Rivera A, Rodriguez DM, Santiago GA, Medina FA, Ellis EM, Torres J, Pobutsky A, Munoz-Jordan J, Paz-Bailey G, Adams 

LE. Epidemiologic Trends of Dengue in U.S. Territories, 2010-2020. MMWR Surveill Summ. 2023 May 19;72(4):1-12.
Seropositive Seronegative

4–16 years

Children/Adolescents

17–60 years

Adults

Is dengue a problem of public health importance 

for adults living in endemic areas?
Fatal dengue cases (N = 68) by age group in 

Puerto Rico, 2010–2020 

Higher mortality rates occurred among adults

*All fatal dengue cases reported during 2010–2020 were from Puerto Rico. No deaths were reported from the other territories

Ryff KR, Rivera A, Rodriguez DM, Santiago GA, Medina FA, Ellis EM, Torres J, Pobutsky A, Munoz-Jordan J, Paz-Bailey G, Adams LE. Epidemiologic Trends of Dengue in U.S. Territories, 2010-2020. MMWR Surveill Summ. 2023 May 19;72(4):1-12.
Summary – Public Health Problem

• Dengue is endemic in six US territories and freely associated 

states.

• Puerto Rico has the largest population among US territories where 

dengue is endemic.

• The highest case and hospitalization rates occur in individuals 

aged 10–19 years.

• The highest mortality rates occur in adults aged ≥20 years.
Public Health Problem

Is the problem (dengue) of public health 

importance?

Options: ○ No ○ Probably no ○ Probably yes ○ Yes ○ Varies ○ Don't know
Benefits and Harms
Benefits and Harms

What is the overall certainty of the 

desirable anticipated effects?
Outcomes: desirable anticipated effects

Outcome Importance* 

Virologically confirmed dengue due to any serotype Critical

Hospitalization for dengue due to any serotype Critical

Dengue hemorrhagic fever due to any serotype Critical

Severe dengue (trial definition) due to any serotype Critical

*Options are critical, important but not critical, not important for decision-making
Systematic review

• Systematic search identified 370 articles

• 17 met inclusion/exclusion criteria including data on outcomes of interest 

from phase 1–3 trials.

• However, 0 articles contained the 57 month follow-up time of interest 

that has been presented to and discussed by Work Group and ACIP. 

• All vaccine efficacy and safety data provided by Takeda.*

*One article regarding safety outcomes used in systematic review has been published (Patel, CID, 2022), but 

data stratified by PICO populations was provided by Takeda in personal communications with WG lead.
Multiple GRADE domains do not change for 

the populations assessed or outcomes.

Outcome No of 

studies

Study 

design Risk of bias Inconsistency Indirectness Imprecision Other 

considerations Certainty

VCD

Hospitalization

DHF

Severe Dengue
Indirectness and imprecision varied by population/outcome 

assessed and determined final certainty level.

Outcome No of 

studies

Study 

design Risk of bias Inconsistency Indirectness Imprecision Other 

considerations Certainty

VCD

Hospitalization

DHF

Severe Dengue

SAE

Deaths
Seropositive Seronegative

4–16 years

Children/Adolescents

• Phase 3 Trial data • Phase 3 Trial data

17–60 years

Adults

How certain are the desirable effects in 

children/adolescents?

*Immunogenicity in seropositive adults is expected to be at least as high as in seronegative adults.
Overall VE

61.2% (56.0, 65.8%)

VE in Seropositives

64.2% (58.4, 69.2%)

VE in Seronegatives

53.5% (41.6–62.9%)

VE in Seropositives by Serotype

DENV-1 56.1% (44.6, 65.2%)

DENV-2 80.4% (73.1, 85.7%)

DENV-3 52.3% (36.7, 64.0%)

DENV-4 70.6% (39.9, 85.6%)

VE in Seronegatives by Serotype

DENV-1 45.4% (26.1, 59.7%)

DENV-2 88.1% (78.6, 93.3%)

DENV-3 -15.5% (-108.2, 35.9%)

DENV-4 -105.6% (-628.7, 42.0%)

Vaccine Efficacy* Outcome: Virologically Confirmed Dengue

*57 months after first dose, significant results bolded. Number for seropositive placebo 

participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714. Paz-Bailey. ACIP, February 17, 2023.
Overall VE

84.1% (77.8, 88.6%)

VE in Seropositives

85.9% (78.7, 90.7%)

VE in Seronegatives

79.3% (63.5, 88.2%)

VE in Seropositives by Serotype

DENV-1 66.8% (37.4, 82.3%)

DENV-2 95.8% (89.6, 98.3%)

DENV-3 74.0% (38.6, 89.0%)

DENV-4 100% (NE, NE)†

VE in Seronegatives by Serotype

DENV-1 78.4% (43.9, 91.7%)

DENV-2 100% (NE, NE)§

DENV-3 -87.9% (-573.4, 47.6%)¶

DENV-4 100 % (NE, NE)**

Vaccine Efficacy* Outcome: Hospitalization

†DENV-4 Placebo events: 3 TAK-003 events: 0

§DENV-2 Placebo events: 23 TAK-003 events: 0

¶DENV-3 Placebo events: 3 TAK-003 events: 11

**DENV-4 Placebo events: 1 TAK-003 events: 0

*57 months after first dose, significant results bolded. Number for seropositive placebo 

participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714. Paz-Bailey. ACIP, February 17, 2023.
Overall VE

84.1% (77.8, 88.6%)

VE in Seropositives

85.9% (78.7, 90.7%)

VE in Seronegatives

79.3% (63.5, 88.2%)

VE in Seropositives by Serotype

DENV-1 66.8% (37.4, 82.3%)

DENV-2 95.8% (89.6, 98.3%)

DENV-3 74.0% (38.6, 89.0%)

DENV-4 100% (NE, NE)†

VE in Seronegatives by Serotype

DENV-1 78.4% (43.9, 91.7%)

DENV-2 100% (NE, NE)§

DENV-3 -87.9% (-573.4, 47.6%)¶

DENV-4 100 % (NE, NE)**

Vaccine Efficacy* Outcome: Hospitalization

†DENV-4 Placebo events: 3 TAK-003 events: 0

§DENV-2 Placebo events: 23 TAK-003 events: 0

¶DENV-3 Placebo events: 3 TAK-003 events: 11

**DENV-4 Placebo events: 1 TAK-003 events: 0

*57 months after first dose, significant results bolded. Number for seropositive placebo 

participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714.

Data insufficient to rule 

out an increased risk 

Paz-Bailey. ACIP, February 17, 2023.
Overall VE

70.0% (31.5, 86.9%)

VE in Seropositives

80.9% (46.3, 93.2%)

VE in Seronegatives

-3.4% (-464.7, 81.1%)

Dengue Hemorrhagic Fever 

(1997 Definition)

*57 months after first dose, significant results for vaccine efficacy bolded. Number for seropositive 

placebo participants 4,855 and vaccine 9,666; Seronegative placebo 1,832 and vaccine 3,714.

Overall VE

70.2% (-24.7, 92.9%)

VE in Seropositives

90.2% (16.4, 98.9%)

VE in Seronegatives

-999.0% (NE, NE)

Severe Dengue

Trial-specific Definition

Events by Serotype

Placebo TAK-003

DENV-1 <10 <10

DENV-2 <10 <10

DENV-3 <10 <10

DENV-4 <10 <10

Total 13 5

Events by Serotype

Placebo TAK-003

DENV-1 <5 <5

DENV-2 <5 <5

DENV-3 <5 <5

DENV-4 <5 <5

Total 2 4

Events by Serotype

Placebo TAK-003

DENV-1 <5 <5

DENV-2 <5 <5

DENV-3 <5 <5

DENV-4 <5 <5

Total 5 1

Events by Serotype

Placebo TAK-003

DENV-1 <5 <5

DENV-2 <5 <5

DENV-3 <5 <5

DENV-4 <5 <5

Total 0 2

Paz-Bailey. ACIP, February 17, 2023.
Outcomes: desirable anticipated effects

Outcome Importance* 

Virologically confirmed dengue due to any serotype Critical

Hospitalization for dengue due to any serotype Critical

Dengue hemorrhagic fever due to any serotype Critical

Severe dengue (trial definition) due to any serotype Critical

*Options are critical, important but not critical, not important for decision-making
What is the overall certainty of the desirable anticipated 

effects in children/adolescents aged 4–16 years?

Outcome (Desirable) Vaccine Efficacy Imprecision Indirectness Certainty

Virologically confirmed dengue 64.2 (58.4, 69.2) Not serious

Hospitalization 85.9 (78.7, 90.7) Not serious

Dengue hemorrhagic fever 80.9 (46.3, 93.2) Not serious

Severe dengue (trial definition) 90.2 (16.4, 98.9) Not serious

Outcome (Desirable) Vaccine Efficacy Imprecision Indirectness Certainty

Virologically confirmed dengue 53.5 (41.6, 62.9) Not serious

Hospitalization 79.3 (63.5, 88.2) Not serious

Dengue hemorrhagic fever -3.4 (-464.7, 818.1) Serious

Severe dengue (trial definition) NE (NE, NE) Serious

Seropositive children/adolescents aged 4–16 years

Seronegative children/adolescents aged 4–16 years
Does the study population differ 

from the population of interest? 
DENV-1 and DENV-2 were the most common 

serotypes in the TAK-003 Phase 3 trial.

Takeda – ACIP WG presentation September 13th

230

193

113

23

0

50

100

150

200

250

1 2 3 4

VCD case counts in Placebo group
All four serotypes have circulated in PR from 

2010–2020.

Ryff KR, Rivera A, Rodriguez DM, Santiago GA, Medina FA, Ellis EM, Torres J, Pobutsky A, Munoz-Jordan J, Paz-Bailey G, Adams 

LE. Epidemiologic Trends of Dengue in U.S. Territories, 2010-2020. MMWR Surveill Summ. 2023 May 19;72(4):1-12.
The VE for all serotypes combined 

from the phase 3 trials 

does not directly apply to our 

population of interest and their 

future risk of dengue if 

it does not protect against one or 

more of the 4 serotypes. 

VE in Seropositives

80.9% (46.3, 93.2%)

VE by Serotype

DENV-1

DENV-2

DENV-3

DENV-4
The VE for all serotypes combined 

from the phase 3 trials 

is only directly applicable to our 

population of interest and their 

future risk of dengue if there is

significant protection against all 4 

serotypes. 

VE in Seropositives

80.9% (46.3, 93.2%)

VE by Serotype

DENV-1

DENV-2

DENV-3

DENV-4
What is the overall certainty of the desirable anticipated 

effects in children/adolescents aged 4–16 years?

Outcome (Desirable) Vaccine Efficacy Imprecision Indirectness Certainty

Virologically confirmed dengue 64.2 (58.4, 69.2) Not serious Not serious High

Hospitalization 85.9 (78.7, 90.7) Not serious Not serious High

Dengue hemorrhagic fever 80.9 (46.3, 93.2) Not serious Serious Moderate

Severe dengue (trial definition) 90.2 (16.4, 98.9) Not serious Serious Moderate

Outcome (Desirable) Vaccine Efficacy Imprecision Indirectness Certainty

Virologically confirmed dengue 53.5 (41.6, 62.9) Not serious Serious Moderate

Hospitalization 79.3 (63.5, 88.2) Not serious Serious Moderate

Dengue hemorrhagic fever -3.4 (-464.7, 818.1) Serious Serious Low

Severe dengue (trial definition) NE (NE, NE) Serious Serious Low

Seropositive children/adolescents aged 4–16 years

Seronegative children/adolescents aged 4–16 years
Seropositive Seronegative

4–16 years

Children/Adolescents

17–60 years

Adults

• Outcomes assessed through 

immunobridging

How certain are the desirable effects in 

adults?
GMR DENV-1 6 months 607 353 0.62 (0.51, 0.76) Yes

GMR DENV-2 6 months 607 355 0.66 (0.57, 0.76) Yes

GMR DENV-3 6 months 607 355 0.98 (0.84, 1.14) Yes

GMR DENV-4 6 months 607 354 1.01 (0.86, 1.18) Yes

Antibody titers in seronegative adults (18–60) were 

noninferior* at 1 and 6 months for almost all serotypes 

compared to participants aged 4–16.

Outcome (desirable) Time after 2nd

dose

N (4–16 

years)

N (18–60 

years)

Geometric Mean Ratio Met noninferiority 

objective*

GMR DENV-1 1 month 641 367 0.69 (0.58, 0.82) Yes

GMR DENV-2 1 month 641 367 0.59 (0.52, 0.66) Yes

GMR DENV-3 1 month 641 367 1.77 (1.53, 2.04) No

GMR DENV-4 1 month 641 367 1.05 (0.92, 1.20) Yes

*Non-inferiority was defined as a geometric mean ratio (GMR) with the upper bound of the 95% CI below 2.0.

Rivera L, Biswal S, Sáez-Llorens X, Reynales H, López-Medina E, Borja-Tabora C, et al. Three years 

efficacy and safety of Takeda's dengue vaccine candidate (TAK-003). Clin Infect Dis. 2021 Oct 4.
What is the overall certainty of the desirable 

anticipated effects in adults aged 17–60 years?

Outcome (Desirable) N (4–16 

years)

N (18–60 

years)

Met noninferiority 

objective

Indirectness Certainty

VCD, hospitalization, 

DHF, severe dengue 

(assessed with 

immunobridging)

607-641 353-367 Yes for all serotypes, 

except for DENV-3 

assessed at 1 month

Serious* Moderate

Seronegative adults aged 17–60 years

*Downgraded once for indirectness due to immunobridging.
Seropositive Seronegative

4–16 years

Children/Adolescents

17–60 years

Adults

• Outcomes assessed through 

immunobridging in 

seronegatives*

• Outcomes assessed through 

immunobridging

How certain are the desirable effects in 

adults?

*Immunogenicity in seropositive adults expected to be at least as robust as in seronegative adults; downgraded twice for indirectness.
What is the overall certainty of the desirable 

anticipated effects in adults aged 17–60 years?

Outcome (Desirable) N (4–16 

years)

N (18–60 

years)

Met noninferiority 

objective

Indirectness Certainty

VCD, hospitalization, 

DHF, severe dengue 

(assessed with 

immunobridging)

607-641 353-367 Yes for all serotypes, 

except for DENV-3 

assessed at 1 month

Serious Moderate

Seronegative adults aged 17–60 years

Outcome (Desirable) Indirectness Certainty

VCD, hospitalization, DHF, severe dengue (assessed with 

immunobridging in seronegative adults)

Very Serious* Low

Seropositive adults aged 17–60 years

*Downgraded twice for indirectness, because outcomes are assessed with immunobridging data from seronegative 

adults and assumption of equal or greater immunogenicity in seropositive adults 
Seropositives Seronegatives

4–16 years

Children/Adolescents

17–60 years

Adults

Summary of Desirable Outcomes

Outcome VE Certainty

VCD 64.2 (58.4, 69.2) High

Hospitalization 85.9 (78.7, 90.7) High

DHF 80.9 (46.3, 93.2) Moderate

Severe dengue 90.2 (16.4, 98.9) Moderate

Outcome (Desirable) Certainty

All outcomes

(assessed with 

immunobridging)

Moderate

Outcome (Desirable) Certainty

All outcomes

(assessed with immunobridging in 

seronegatives*)

Low

*Immunogenicity in seropositive adults is expected to be at least as high as in seronegative adults.

Outcome VE Certainty

VCD 53.5 (41.6, 62.9) Moderate

Hospitalization 79.3 (63.5, 88.2) Moderate

DHF -3.4 (-464.7, 818.1) Low

Severe dengue NE (NE, NE) Low
Seropositives Seronegatives

4–16 years

Children/Adolescents

17–60 years

Adults

Summary of Certainty for All Desirable Outcomes

*Immunogenicity in seropositive adults is expected to be at least as high as in seronegative adults.

High – Moderate Moderate – Low

Low Moderate
Benefits and Harms

How substantial are the desirable 

anticipated effects?
The population level effects of TAK-003 

implementation will vary by...

seroprevalence of past infection AND serotype circulation.

Anti-DENV IgG

1 2 3 4
Preliminary Modeled Estimates of Populationlevel Impacts in San Juan, PR* over 10 years

Recommendation Reduction in VCD† Reduction in hospitalizations†

4–16, seropositive (screening‡) 1% 3%

4–16, all serostatuses (no screening) 3% 3%

17–60, seropositive (screening‡) 6% 10%

17–60, all serostatuses (no screening) 8% 13%

4–60, seropositive (screening‡) 7% 12%

4–60, all serostatuses (no screening) 9% 15%

España. ACIP, June 22, 2023.

*The model assumes a seroprevalence of 40% at age 9, a vaccine coverage increasing from 0 to 40% over 10 years in all ages eligible, and 

serotype distribution simulated from 20 years of historical data (1996–2016) from San Juan, Puerto Rico (PR).

†Averted symptomatic and hospitalizations are for all ages in San Juan and include direct and indirect effects. 

‡Screening test with 80% sensitivity and 98% specificity
Summary of Desirable Anticipated Effects

• Modeling* shows a reduction in VCD and hospitalizations following 

implementation of TAK-003 in all populations explored in the policy 

questions.

• Reductions in VCD and hospitalizations are higher when vaccination is 

implemented in broader age ranges and for both seropositive and 

seronegative individuals. 

*Model based on preliminary data from Dr. España presented to ACIP on June 22, 2023.
Benefits and Harms

How substantial are the desirable 

anticipated effects?

Options: ○ Minimal ○ Small ○ Moderate ○ Large ○ Varies ○ Don't know
Benefits and Harms

How substantial are the undesirable 

anticipated effects?

What is the overall certainty?
Outcomes: undesirable anticipated effects

Outcome Importance* 

Serious adverse events (SAEs) Critical

Deaths Critical

Systemic reactions†Important

Local reactions†Important

Interference with co-administered vaccines†Important

*Options are critical, important but not critical, not important for decision-making

†Not assessed in GRADE analysis
Seropositive Seronegative

4–16 years

Children/Adolescents

• Phase 2 and 3 trials • Phase 2 and 3 trials

17–60 years

Adults

How certain are the undesirable effects in 

children/adolescents?

*Immunogenicity in seropositive adults is expected to be at least as high as in seronegative adults.
What is the overall certainty of the undesirable anticipated 

effects in children/adolescents aged 4–16 years?

Seropositive children/adolescents aged 4–16 years

Seronegative children/adolescents aged 4–16 years

Outcome 

(Undesirable)

n/N TAK-003 n/N placebo Hazard Ratio Imprecision Indirectness Certainty

SAEs 826/9725 (8.5%) 503/4944 (10.2%)* 0.82 (0.74, 0.92) Not serious Not serious High

Deaths† 14/9725 (0.14%) 6/4944 (0.12%) 1.18 (0.45, 3.07) Not serious Not serious High

Outcome 

(Undesirable)

n/N TAK-003 n/N placebo Hazard Ratio Imprecision Indirectness Certainty

SAEs 323/3984 (8.1%) 183/1979 (9.3%)* 0.88 (0.73, 1.05) Not serious Not serious High

Deaths† 2/3984 (0.05%) 1/1979 (0.05%) 1.00 (0.09, 11.04) Not serious Not serious High

*Higher dengue SAEs in placebo (n=100) compared to TAK-003 (n=51) resulted in HR <1 for all SAEs in TAK-003 compared to placebo.

†None of the deaths in the trial were due to dengue

Communication with Takeda. April 25, 2023.
Seropositive Seronegative

4–16 years

Children/Adolescents

• Phase 2 and 3 trials • Phase 2 and 3 trials

17–60 years

Adults

• Phase 2 and 3 trials • Phase 2 and 3 trials

How certain are the undesirable effects in 

adults?
What is the overall certainty of the undesirable 

anticipated effects in adults aged 17–60 years?

Seronegative adults aged 17–60 years

Seropositive adults aged 17–60 years

Outcome 

(Undesirable)

n/N TAK-003 n/N placebo Hazard Ratio Imprecision Indirectness Certainty

SAEs 9/488 (1.8%) 3/84 (3.6%) 0.499 (0.14, 1.84) Not serious Not serious High

Deaths 0/488 0/84 N/A Not serious Not serious High

Outcome 

(Undesirable)

n/N TAK-003 n/N placebo Hazard Ratio Imprecision Indirectness Certainty

SAEs 3/83 (3.6%) 0/31 N/A Serious Not serious Moderate

Deaths 0/83 0/31 N/A Serious Not serious Moderate

Communication with Takeda. April 25, 2023.
Seropositives Seronegatives

4–16 years

Children/Adolescents

17–60 years

Adults

Summary of Undesirable Outcomes Certainty

Outcome 

(Undesirable)

n/N TAK-003 n/N placebo Certainty

SAEs 3/83 (3.6%) 0/31 Moderate

Deaths 0/83 0/31 Moderate

Outcome 

(Undesirable)

n/N TAK-003 n/N placebo Certainty

SAEs 826/9725 

(8.5%)

503/4944 

(10.2%)

High

Deaths 14/9725 

(0.14%)

6/4944 

(0.12%)

High

Outcome 

(Undesirable)

n/N TAK-003 n/N placebo Certainty

SAEs 323/3984 

(8.1%)

183/1979 

(9.3%)*

High

Deaths 2/3984 

(0.05%)

1/1979 

(0.05%)

High

Outcome 

(Undesirable)

n/N TAK-003* n/N placebo Certainty

SAEs 9/488 (1.8%) 3/85 (3.6%) High

Deaths 0/488 0/85 High
Seropositives Seronegatives

4–16 years

Children/Adolescents

17–60 years

Adults

Summary of Certainty for All Undesirable Outcomes

High High

Moderate High
Dengue vaccine outcomes of interest can be a 

desirable and an undesirable outcome.

Desirable Effects Undesirable Effects

Prevent Dengue Enhance Dengue?
Desirable Effects Undesirable Effects

Seropositives

DENV-1

DENV-2

DENV-3

DENV-4

Seronegatives

DENV-1

DENV-2

Prevent Dengue

Seronegatives

DENV-3*

The effects differ by vaccinee serostatus 

and serotype.

“Data insufficient to 

rule out an increased 

risk among vaccine 

recipients.”

*for outcome of hospitalization.

Enhance Dengue?
Benefits and Harms

Do the desirable effects outweigh the 

undesirable effects?
*Hospitalizations among vaccinees in a no screening scenario represent hospitalizations among seronegative persons who are infected by 

DENV-3 post-vaccination. In the screening scenario, they represent hospitalizations among seronegative persons with false positive test results 

who are infected with DENV-3 and are subsequently hospitalized. Model based on 40% seroprevalence at 9 years old. Other model 

assumptions described by Dr. España (ACIP, June 22, 2023).

Screening decreased the ratio of averted to additional hospitalizations compared to no prevaccination screening but may lead to lower absolute hospitalizations averted. 

0

10

20

30

40

50

60

70

80

90

100

1 2 3

Ratio of hospitalizations averted to

additional hospitalizations

*

6:1

15:1

35:1

18:1

102:1

69:1
Summary of Balance of Desirable and 

Undesirable Anticipated Effects

• Modeling* shows that the ratio of hospitalizations averted to additional 

hospitalizations caused by vaccination increases with screening and 

vaccination of seropositive individuals only.

• This ratio is higher in the population aged 17–60 years compared to the 

population aged 4–16 years under both screening and no screening 

scenarios.

• The benefits of screening and vaccinating seropositive individuals will be 

weighed against the lower overall reduction in VCD and hospitalizations in 

this scenario.

*Models based on preliminary data from Dr. España presented to ACIP on June 22, 2023.
Benefits and Harms

Do the desirable effects outweigh the 

undesirable effects?

Options: ○ Favors intervention ○ Favors comparison ○ Favors both ○ Favors neither ○ Varies ○ Don't know 
Resource Use

Is the intervention a reasonable and 

efficient allocation of resources?
Preliminary Modeled Estimates of Costeffectiveness in San Juan, PR over 10 years

Population and Strategy†

ICER per hospitalization 

averted (USD) §

ICER per QALY gained (USD)§¶

4–16 (screening) 16,800 181,918

4–16 (no screening) 46,813 254,751

17–60 (screening) 48,989 396,574

17–60 (no screening) 39,886 314,597

4–60 (screening) 48,305 384,830

4–60 (no screening) 45,495 326,412

España. ACIP, June 22, 2023.

Estimates modeled on San Juan, PR, population 326,953. Puerto Rico has a total population of 3.264 million) (US Census Bureau). For estimates with screening, the model assumes 

a test with 80% sensitivity and 98% specificity.

†The model assumes a seroprevalence of 40% at age 9 and a vaccine coverage increasing from 0 to 40% over 10 years. 

§Cost of full vaccination was $330 US; cost of a test was $30 with annual retesting for negative individuals.

¶ICER per QALY gained was modeled from a societal perspective with a 3% discounting rate. 
Resource Use

Is the intervention a reasonable and 

efficient allocation of resources?

Options: ○ No ○ Probably no ○ Probably yes ○ Yes ○ Varies ○ Don't know
Summary

• Presented 3 of 7 EtR domains:

• Public Health Problem

• Benefits and Harms

• Resource Use

• Certainty assessment of the evidence for outcomes by policy question 

ranged from high to low.

• Weighing the risks and benefits of dengue vaccination is complex.

• Work Group discussions will continue this summer.

• Draft recommendation and vote will occur at the next meeting.
For more information, contact CDC

1-800-CDC-INFO (232-4636)

TTY: 1-888-232-6348 www.cdc.gov

The findings and conclusions in this report are those of the authors and do not necessarily represent the 

official position of the Centers for Disease Control and Prevention.

ACIP Members

Wilbur Chen (Chair)

Kathy Poehling

Beth Bell

Veronica McNally

CDC Co-Leads

Gabriela Paz-Bailey

Laura Adams

Ex Officio Members

Kaitlyn Morabito (NIH)

Ralph LeBlanc (FDA)

Ihid Carneiro Leao (FDA)

Kirk Prutzman (FDA)

Srihari Seshadri (DOD)

Liaison Representatives

Elizabeth Barnett (AAP)

Rob Schechter (AIM)

Consultants

Edwin Asturias

Robert Atmar

Alan Barrett

Iris Cardona

Anna Durbin

Tony Marfin

Kristen Pierce

Anita Shet

CDC Contributors

Joshua Wong

Nicole Medina

Mimi Eckert

Rachel Eidex

Alfonso Hernandez

Susan Hills

Terri Hyde

Mike McNeil

Jorge Munoz

Erin Staples

Cindy Weinbaum

Rita Helfand

GRADE Consultants

Doug Campos-Outcalt

Rebecca Morgan

GRADE Analysis Team

Joshua Wong (Co-lead)

Alfonso Hernandez (Co-Lead)

Cameron Adams

Arlene Rivera

Daniel Milan

Questions? ACIP Dengue Vaccines Workgroup and Support Team